Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.

Guidelines and preventive measures have been established to limit radiation exposure time during modified barium swallow studies (MBSS) but multiple variables may influence the duration of the exam. This study examined the influence of clinician experience, medical diagnosis category, swallowing impairment severity, and use of a standardized protocol on fluoroscopy time. A retrospective review of 739 MBSSs performed on 612 patients (342 males/270 females; age range = 18-96 years) completed in 1 year at the Medical University of South Carolina was performed with IRB approval. All studies were completed by speech-language pathologists trained in the data collection protocol, interpretation, and scoring of the MBSImP™(©). Medical diagnosis category, swallowing impairment severity (MBSImP™(©) score), clinician experience, and fluoroscopy time were the variables recorded for analysis. Fluoroscopy time was not significantly associated with medical diagnosis category (p = 0.10). The severity of the MBSImP™(©) Oral Total and Pharyngeal Total resulted in statistically significant increases in fluoroscopy time (p < 0.05). Studies by novice clinicians had longer exposure times when compared to those of experienced clinicians (p = 0.037). Average radiation exposure time using the MBSImP™(©) approach was 2.9 min, with a 95 % confidence interval of 2.8-3.0 min, which was well within the range of exposure times reported in the literature. This study provides preliminary information regarding the impact of medical diagnosis category, swallowing impairment severity, and clinician experience on fluoroscopy time. These findings also suggest that a thorough, standardized protocol for MBSSs did not cause unnecessary radiation exposure time during the MBSS.

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.

Translating evidence-based HIV/STD prevention interventions and research findings into applicable HIV prevention practice has become an important challenge for the fields of community psychology and public health due to evidence-based interventions and evidence-based practice being given higher priority and endorsement by federal, state, and local health department funders. The Interactive Systems Framework (ISF) for Dissemination and Implementation and the Division of HIV/AIDS Prevention (DHAP) Research-to-Practice model both address this challenge. The DHAP model and the ISF are each presented with a brief history and an introduction of their features from synthesis of research findings through translation into intervention materials to implementation by prevention providers. This paper describes why the ISF and the DHAP model were developed and the similarities and differences between them. Specific examples of the use of the models to translate research to practice and the subsequent implications for support of each model are provided. The paper concludes that the ISF and the DHAP model are truly complementary with some unique differences, while both contribute substantially to addressing the gap between identifying effective programs and ensuring their widespread adoption in the field.

OBJECTIVE: Post-emergency department triage of older trauma patients continues to be challenging, as morbidity and mortality for any given level of injury severity tend to increase with age. The comorbidity-polypharmacy score (CPS) combines the number of pre-injury medications with the number of comorbidities to estimate the severity of comorbid conditions. This retrospective study examines the relationship between CPS and triage accuracy for older (≥45y) patients admitted for traumatic injury. METHODS: Patients aged 45y and older presenting to level 1 trauma center from 2005 to 2008 were included. Basic data included patient demographics, injury severity score, morbidity and mortality, and functional outcome measures. CPS was calculated by adding total numbers of comorbid conditions and pre-injury medications. Patients were divided into three triage groups: undertriage (UT), appropriate triage (AT), and overtriage (OT). UT criteria included initial admission to the floor or step-down unit followed by an unplanned transfer to intensive care unit (ICU) within 24h of admission. OT was defined as initial ICU admission for <1d without stated need for ICU level of care (i.e., lack of evidence for tracheal intubation or mechanical ventilation, injury-related hemorrhage, or other traditional ICU indications, such as intracranial bleeding). All other patients were presumed to be correctly triaged. The three triage groups were then analyzed looking for contributors to mistriage. RESULTS: Charts for 711 patients were evaluated (mean age, 63.5y; 55.7% male; mean ISS, 9.02). Of those, 11 (1.55%) met criteria for UT and 14 (1.97%) for OT. The remaining 686 patients had no evidence of mistriage. The three groups were similar in terms of injury severity and GCS. The groups were significantly different with respect to CPS, with UT CPSs (14.9±6.80) being nearly three times higher than OT CPSs (5.14±3.48). There were more similarities between AT and OT groups, with the UT group being characterized by greater number of complications and lower functional outcomes at discharge (all, P<0.05). The UT group had significantly higher mortality (27%) than the AT and OT groups (6% and 0%, respectively). CONCLUSIONS: In the era of medication reconciliation, CPS is easy to obtain and calculate in patients who are not critically injured. This study suggests that CPS may be a promising adjunct in identifying older trauma patients who are more likely to be undertriaged. The significance of our findings is especially important when considering that injury severity in the UT group was similar to that in the other groups. Further evaluation of CPS as a triage tool in acute trauma is warranted.

Background. An early sign of ventricular remodeling is increased left ventricular mass (LVM) which over time may lead to left ventricular hypertrophy, the strongest predictor of cardiovascular morbidity and mortality, other than advancing age. Methods. 62 (30 TM; 32 CTL) African American adolescents (age 16.2 ± 1.3 years) with high normal systolic BP were randomly assigned to either 4-month Transcendental Meditation (TM) or health education control groups. The echocardiographic-derived measure of LVM index (LVMI = LVM/ht(2.7)) was measured before and after the 4-month TM study and at 4-month followup. 2D-guided M-mode echocardiography using a Hewlett Packard 5500 echosonograph was used to determine LVMI. Results. The TM group exhibited a greater decrease in LVMI at 4-month followup compared to the CTL group (-2.6 versus +0.3 gm/ht(2.7), P < 0.04). The TM group exhibited a lesser increase in BMI at 4-month follow-up compared to the CTL group (0.2 ± 1.6 versus 1.1 ± 1.4, P < 0.03). Conclusion. These findings indicate that among a group of prehypertensive African American adolescents, 4 months of TM compared to heath education resulted in a significant decrease in LVMI, and these changes were maintained at 4-month follow-up.

BACKGROUND: A critical aspect of clinical and translational science (CTS) is interdisciplinary and collaborative research, which increasingly requires a wide range of computational and human resources. However, few studies have systematically analyzed such resource needs of CTS researchers. OBJECTIVE: To improve our understanding of CTS researchers' needs for computational and human resources in order to build useful and useable supporting informatics tools. METHODS: We conducted semistructured interviews of 30 CTS researchers from the University of Michigan, followed by qualitative analysis of the interview transcripts. RESULTS: The analysis identified three recurring themes: the need for the federation of information, the need to address information overload, and the need to humanize computing, including strong and well-informed views about the use of social networking tools for research collaboration. These findings helped us to narrow down the available design choices for assisting CTS researchers, and helped to identify potential deficiencies of well-known theoretical frameworks used to guide our study, with suggestions for future remedies. CONCLUSIONS: The user needs identified through the study, along with concrete design suggestions, provided key design, methodological, and theoretical insights, which are being used to guide the design and development of a CTS resource portal. The results and interview instrument should be useful to other institutions with Clinical and Translational Science Awards that face similar challenges related to helping CTS researchers make more effective use of computational and human resources.

Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20-30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Two HER2-directed therapies have been approved by the United States Food and Drug Administration for the treatment of HER2-overexpressing breast cancer: trastuzumab, a humanized monoclonal antibody against the extracellular portion of HER2; and lapatinib, a dual HER2- and epidermal growth factor receptor-specific tyrosine kinase inhibitor. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance. Currently, several mechanisms of resistance have been described, including mutations in other signaling pathways, expression of a truncated form of HER2, receptor crosstalk, and autophagy. There are several approaches under study to target these pathways of resistance, including blocking PI3 kinase and mammalian target of rapamycin signaling, blocking neoangiogenesis and the vascular endothelial growth factor axis, using monoclonal antibody targeting of the HER2 dimerization site, and using HER2 monoclonal antibody-drug conjugates. Here we will review the current scientific rationale for these agents and how combinations of these agents may yield additive or synergistic effects and lead to improved outcomes for patients with HER2-amplified breast cancer.

New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.

A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.